Project Summary Alcohol use disorder (AUD) is a significant public health problem in the United States. Binge pattern consumption, the most common form of AUD, damages corticolimbic brain regions essential for cognition and behavioral control, including the hippocampus. Compared to men, women disproportionately experience alcohol-related health problems, including organ damage, and a growing body of research indicates that they are also more likely than men to suffer alcohol-induced brain damage. The apparent vulnerability of the female brain to alcohol necessitates a more thorough understanding of underlying mechanisms, to inform the development of effective treatment strategies. Our preliminary data from a rat model show sex-dependent effects of binge alcohol on the hippocampus and hippocampal-dependent cognition, with females significantly more negatively affected, and our proposed experiments will develop this model. The traditional suspects when investigating sex differences are gonadal hormones, either due to their permanent, organizational effects or their transient, activational (circulating) effects. Because circulating ovarian hormones are protective against other forms of brain injury, such as stroke, the vulnerability of the female brain to alcohol damage presents a conundrum. To resolve it, our proposed experiments will test the novel hypothesis that early organizational (but not circulating) sex hormone effects are responsible for the selective vulnerability of the female brain to binge alcohol exposure. Finally, although the female hippocampus may be selectively vulnerable to binge alcohol, we have also found that it can be repaired by exercise. We will use this model of exercise-driven repair to probe underlying mechanisms and address the novel question of whether the repaired hippocampus functions like the never-damaged hippocampus. Using a clinically-relevant rodent model, our three specific aims will 1) establish the selective vulnerability of the female brain to binge alcohol; 2) determine the contribution of organizational and/or circulating sex hormone effects and 3) pinpoint mechanisms and efficacy of exercise- driven restoration. Our findings will elucidate the mechanisms underlying female brain susceptibility to alcohol damage and inform the development of novel interventions to enhance brain repair.